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Revised Model Of Protein-Drug Interactions Could Make Job Of Drug Designers A Little Easier

Date:
February 17, 2000
Source:
University Of California, Berkeley
Summary:
While most people may have difficulty distinguishing a person from his or her mirror image, proteins in cells have no such problem. They are exquisitely selective, able to latch on tightly to one molecule but reject its mirror image. Now scientists claim that a 50-year-old theory explaining how proteins and enzymes discriminate so precisely, considered gospel by most researchers, needs revision.

By Robert Sanders, Public Affairs

BERKELEY -- While most people may have difficulty distinguishing a person from his or her mirror image, proteins in cells have no such problem. They are exquisitely selective, able to latch on tightly to one molecule but reject its mirror image.

Now scientists claim that a 50-year-old theory explaining how proteins and enzymes discriminate so precisely, considered gospel by most researchers, needs revision.

The finding could significantly help drug designers, who may needlessly be discarding good drug candidates because of this misconception.

"The reigning theory of how enzymes distinguish between very slight differences in molecules is the three-point attachment model found in essentially all biochemistry textbooks," said Daniel E. Koshland Jr., professor of molecular and cell biology at the University of California, Berkeley, and a researcher in the Center for Advanced Materials at Lawrence Berkeley National Laboratory.

"This is very important in pharmacology, where drug designers rely on the theory to design a particular mirror image, or enantiomer, to fit exactly into the active site of an enzyme or receptor. Well, the classic explanation needs correction."

In a paper in the Feb. 10 issue of Nature, Koshland and Andrew D. Mesecar, a former postdoctoral fellow at UC Berkeley and now an assistant professor in the Department of Medicinal Chemistry and Pharmacognosy and the Center for Pharmaceutical Biotechnology at the University of Illinois, Chicago, argue that the so-called Ogsdon three-point attachment model must be replaced by a new four-point location model.

These models explain how proteins bind to "chiral" molecules, that is, molecules that cannot be superimposed on their mirror image. Typically the mirror-image versions of chiral molecules act very differently in the body. Some bacteria can degrade one version of a pollutant but not its mirror image; a key receptor in the brain is turned on by an amino acid but not its mirror image.

The reigning assumption is that the business end of a molecule homes in on the "active site" of a protein - an enzyme, for example, or a receptor sitting on the surface of a cell - and makes a three-point landing. That is, three groups arranged around a tetrahedral carbon atom at the business end interact with three locations in the active site, usually with such precision that no other alignment would work.

In fact, Koshland and Mesecar say, a three-point landing is not sufficient to allow a protein to discriminate between mirror images of the incoming molecule. While one molecule could fit snugly in the active site from the front, for example, the mirror image might fit just as well coming in from the rear.

Some other attribute of the active site determines whether it specifically binds one or the other mirror image. Sometimes it is a constraint, such as an obstacle preventing binding from one direction. Often it is a fourth interaction in the active site, for example with a metal ion, that turns the encounter into a four-point landing.

"We usually thought there was only one binding mode at an active site of a protein," said Mesecar. "This shows you can have at least two. Selection is dependent on the active site environment of the protein."

This new way of looking at protein interactions would significantly affect drug designers, who, Koshland says, may needlessly be discarding good drug candidates because of this misunderstanding.

Juggling three-dimensional computer models of enzymes or receptors, drug designers typically engineer small molecules to fit just so into a particular active site, with such precision that even the mirror image wouldn't fit. The goal is to switch a receptor on or off or disable an enzyme in hopes of stopping some disease process.

However, assuming only one of two mirror images of a drug will bind strongly, when in fact both may bind to the active site, can lead to confusing assays and possible rejection of a promising drug candidate.

"What we are saying is, you never really know whether one or both mirror images are capable of binding in the active site," Mesecar said. "People are going to have to revise their thinking. This may change the way they interpret their binding data for enantiomers."

"To really do it right with designing drugs, you must think in terms of four points, not three," Koshland said.

In their paper they detail one specific example of how this works. The enzyme isocitrate dehydrogenase has the sole purpose of grabbing hold of isocitrate and breaking it down as one link in the citric acid cycle, or Krebs cycle, that generates energy for the cell.

Until now, it was thought that only one form of isocitrate (the D isomer) was able to make a three-point landing in the active site of IDH and hold on tightly.

Koshland and Mesecar found that in the absence of magnesium ions, the enzyme latches on preferentially to the other, inactive form of isocitrate (the L isomer). Only when magnesium is present does it bind the active isomer, and go on to generate the energy of the cell.

In fact, when the enzyme binds to L-isocitrate the cycle stops dead in its tracks and generates no energy. This implies that the interaction between the enzyme and D-isocitrate evolved in the presence of magnesium ions.

"This work shows how important metals are in molecular discrimination between mirror-image molecules," Mesecar said, and is further evidence that metals like magnesium, zinc, chromium and copper - always known to be critical in the diet, if in minuscule amounts - play a major role in the molecular machinery of the cell.

Koshland notes that other enzymes have been shown recently to bind equally well to both mirror image molecules. In some cases, one enantiomer is the actual substrate - the molecule the enzyme is designed to react with while the other acts as an inhibitor.

The work was funded by the National Science Foundation.


Story Source:

The above story is based on materials provided by University Of California, Berkeley. Note: Materials may be edited for content and length.


Cite This Page:

University Of California, Berkeley. "Revised Model Of Protein-Drug Interactions Could Make Job Of Drug Designers A Little Easier." ScienceDaily. ScienceDaily, 17 February 2000. <www.sciencedaily.com/releases/2000/02/000217083253.htm>.
University Of California, Berkeley. (2000, February 17). Revised Model Of Protein-Drug Interactions Could Make Job Of Drug Designers A Little Easier. ScienceDaily. Retrieved September 30, 2014 from www.sciencedaily.com/releases/2000/02/000217083253.htm
University Of California, Berkeley. "Revised Model Of Protein-Drug Interactions Could Make Job Of Drug Designers A Little Easier." ScienceDaily. www.sciencedaily.com/releases/2000/02/000217083253.htm (accessed September 30, 2014).

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